DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2019/0864 70, filed 12/19/2019, which claims the priority benefit of EP Application No. 18306783.4, filed 12/20/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/21/2021, 05/18/2023,
09/19/2023, 10/16/2023 and 08/13/2024 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claims 1, and 23-34 are pending in this application and are currently under examination. Claims 1, 23, 25, 29-30 and 34 have been amended. Claims 2-22 have been cancelled by applicant without prejudice or disclaimer.
Applicant’s arguments, filed 07/08/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 04/08/2026 Office Action and modified in order to address the most recent amendments.
Claim Interpretation
Claim 1 of the instant claims is being interpreted by the examiner as a method of treating
a patient with cancer by 1.) measuring miR-124 in the patient and 2.) administering the compound of 8-chloro-N-( 4-(trifluoromethoxy )phenyl)quinolin-2-amine.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The limitations of claim 23 are drawn to the limitations of “comparing a measured expression level of miR-124 in the patient to the control reference value”, which fails to limit the scope of the limitation “measuring a reduced and/or modulated presence and/or a reduced and/or modulated expression level of miR-124 in the patient as compared to a control reference value” in the first portion of independent claim 1 (lines 3-5) and appears to merely repeat the limitation without further narrowing the scope. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 25 is dependent on claim 1 and drawn to a control sample taken from the patient prior to treatment or prior to the presence of the cancer, which is a broader limitation than independent claim 1 in which the patient has been previously selected from a population with cancer. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
This rejection may be overcome by amending the scope of the claims to the patient
population established in claim 1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, and 23-34 are rejected under 35 U.S.C. 103 as being unpatentable over Tazi et al. (WO 2014/111892 Al) in view of Roux et al. (WO 2010/143168 A2).
The instant claims are directed to a method of treating a patient with stomach, gastric, gastrointestinal, colorectal, pancreas, lung, and liver cancer by first measuring miR-124 followed by administering a compound of 8-chloro-N-( 4-(trifluoromethoxy )phenyl)quinolin-2-amine.
Tazi et al. teach in an embodiment, a quinoline derivative of the invention may be 8- chloro-N-[ 4-( trifluoromethoxy )phenyl] quinolin-2-amine (Below) wherein the invention concerns a use of at least one miRNA, said at least one miRNA being miR-124, as a biomarker of an activity of a quinoline derivative (pg. 8, lines 1-7). Tazi teaches an unexpected observation that a treatment with quinoline derivatives, such as quinoline derivatives of formula (I) or (II), and in particular with the 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, resulted in the removal of the viruses and in a dramatic increase (13-fold relative to control) of miR-124 expression.
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Tazi’s Compound 1
8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (Above)
Tazi discloses "The oncoviruses are thus termed because they can be associated with cancers and malignant infections. There may be mentioned, for example, leukemogenic viruses (such as the avian leukemia virus (AL V), the murine leukemia virus (MUL V), also called Moloney virus, the feline leukemia virus (FEL V), human leukemia viruses such as HTL VI and HTL V2, the simian leukemia virus or STL V, the bovine leukemia virus or BL V, the primate type D oncoviruses, the type B oncoviruses which are inducers of mammary tumors, or oncoviruses which cause a rapid cancer (such as the Rous sarcoma virus or RSV)." (pg. . 1, lines 28-34). Tazi also teaches measuring a presence or an expression level of miR-124 in a biological sample previously obtained from said patient, and comparing said presence or expression level to a control reference value, wherein a modulated presence or level of expression of said miRNA relative to said control reference value. As well as a method of assessing an activity of a quinoline derivative by "a- measuring a presence or an expression level of at least one miRNA, said at least one miRNA being miR-124, in a first biological sample previously obtained from said patient before administering said quinoline derivative and in a second biological sample previously obtained from said patient after administering said quinoline derivative; and b - determining if said presence or expression level is modulated in the second biological sample obtained after the treatment as compared to the second biological sample obtained before the treatment; wherein a modulated presence or level of expression of said miRNA is indicative of an activity of said quinoline derivative." (pgs. 8, line 19- pg. 9, line 5) Tazi also discloses the measured level expression of miR-124 may be at least a two-fold, preferably at least a four-fold, preferably at least a six-fold, preferably at least an eight-fold, and more preferably at least a ten-fold decrease relative to said control reference value (pg. 12, lines 13-15). Tazi also discloses the miR-124 biomarker may be used to monitor or manage quinoline derivatives of formula (I) activity during patient treatment (pg. 13, lines 8-9). Tazi teaches "A method of assessing or monitoring the activity of a quinoline derivative of formula (I) in a patient treated with the quinoline derivative may involve measuring a level of expression of miR-124 in an isolated sample, preferably isolated PBMC (Peripheral Blood Mononuclear Cell), and comparing the measured level of expression to a level of expression of miR-124 in an isolated an isolated sample taken from the patient prior to the treatment. By following the miR-124 level, the activity of the quinoline derivative can be monitored over time (pg. 13, lines 12-17). Tazi also teaches In some embodiments, control samples are taken from the patient prior to treatment or prior to the presence of the disease (such as an archival blood sample). In other embodiments, the control samples are taken from a set of normal, non-diseased members of a population (pg. 16, lines 18-21).
However, Tazi et al. fail to disclose an explicit example of treating a cancer by
administering the compound of 8-chloro-N-[ 4-(trifluoromethoxy )phenyl]quinolin-2-amine.
Roux et al. teach that the invention is in keeping with the evidence as published during the last twenty years of a link between changes in RNA alternative splicing and metastatic invasion which has opened to new therapeutic strategies (pg. 1, lines 25-2 7). Roux also teaches It has now been found that derivatives of formula (I) as defined in formula (I) hereinafter are able to correct defects of alternative splicing, as illustrated in the experimental data hereinafter, a mechanism closely associated with the invasive progression of metastatic cancers, and on the basis of such activity, the compounds are useful in the treatment of cancer. The present invention therefore relates to compounds of formula (I) as defined below for use as agents for preventing, inhibiting or treating cancer. (pg. 1, line 30-pg. 2, line 4). Tazi discloses a derivative of formula Ib as 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine compound 90 (pg. 43)
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Roux’s Compound 90 (Above).
Roux also discloses that colorectal cancer, pancreatic cancer, lung cancer, including non-small cell lung cancer, and liver cancer are cancers which can be treated by compounds of the invention (pg. 77, lines 6-13).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer the compound of 8-chloro-N-[ 4-(trifluoromethoxy)phenyl]quinolin-2-amine to a patient with colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer by using miR-124 as a biomarker to monitor the efficacy of 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine in treating oncoviruses as taught by Tazi because Roux disclosed 8-chloro-N-[4-(trifluoromethoxy)phenyl] quinolin-2-amine as a treatment for a patient with colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer. See MPEP 2144.05(11)
A person of ordinary skill in the art would have been motivated to treat colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer with a compound of 8-chloro-N-[ 4-(trifluoromethoxy )phenyl]quinolin-2-amine as disclosed by Roux while monitoring and adjusting treatment based on patients response to treatment using miR-124 as a biomarker to monitor efficacy of 8-chloro-N-[ 4-(trifluoromethoxy )phenyl]quinolin-2-amine as taught by Tazi and would have given a skilled artisan a reasonable expectation of success in treating cancer.
Response to Arguments
Applicant's arguments filed 07/08/2026 have been fully considered but they are not persuasive.
Rejection Under 35 U.S.C. § 112(d)
Applicant argues that the Office Action is correct that claim 1 relates to treating a patient that is suffering from cancer, where the cancer patient is selected by "measuring a reduced and/or modulated presence and/or a reduced and/or modulated expression level of miR-124 in the patient." However, claims 25 and 26 do not relate to the cancer patient's biological sample that is assayed in claim 1, but rather relate to a "control sample" from which "a control reference value" is measured for comparison to the measured expression level of miR-124 in the cancer patient's biological sample. Thus, the control sample in claims 25 and 26 is different from the cancer patient's biological sample that assayed in claim 1. As such, the control sample of claims 25 and 26 can be, for example, an archival sample that was taken from the patient prior to the presence of cancer.
The examiner agrees the control reference value may come from a control sample and that it is possible the sample is taken from normal, non-diseased members of a population. However, independent claim 1 establishes that the patient population is “a patient suffering from cancer” (Line 2), and therefore the limitation of dependent claim 25 wherein “the control sample is taken from the patient” (lines 1-2) contradicts and expands the limitations of independent claim 1 to now include a control sample from a patient with cancer prior to the patient having cancer and thereby expanding the patient population as the claims are currently written.
Rejection Under 35 U.S.C. § 103
Applicant argues the applied references of TAZI and Roux do not teach or suggest the claim feature of “Selecting a patient suffering from cancer for a treatment by measuring a reduced and/or modulated presence and/or a reduced and/or modulated expression level of miR-124 in the patient as compared to a control reference value." Applicant also argues none of the applied references teaches or suggests "selecting a patient suffering from cancer for a treatment by measuring a reduced and/or modulated presence and/or a reduced and/or modulated expression level of miR-124 in the patient as compared to a control reference value," as recited by claim 1.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As recited in the claim interpretation section in the Non-final rejection dated 04/08/2026 and as written above, “ Claim 1 of the instant claims is being interpreted by the examiner as a method of treating a patient with cancer by 1.) measuring miR-124 in the patient and 2.) administering the compound of 8-chloro-N-( 4-(trifluoromethoxy )phenyl)quinolin-2-amine.”
Tazi teaches administering the compound of 8-chloro-N-( 4-(trifluoromethoxy )phenyl)quinolin-2-amine to a patient and the steps of:
a- measuring a presence or an expression level of at least one miRNA, said at least one miRNA being miR-124, in a biological sample previously obtained from said patient; and
b- comparing said presence or expression level to a control reference value, wherein a modulated presence or level of expression of said miRNA relative to said control reference value is indicative of a viral infection.
This satisfies the active steps for the “selecting” portion of claim 1 and Roux teaches “[t]he following type of cancer may more particularly be treated by the compounds according to the present invention: colorectal cancer, pancreatic cancer, lung cancer 10 including non-small cell lung cancer, breast cancer, bladder cancer, gall bladder cancer, thyroid cancer, melanoma, liver cancer, uterine/cervical cancer, oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer, head and neck cancer, and stomach cancer, etc.” (pg. 77 lines 8-13).
A person of ordinary skill would have administered 8-chloro-N-( 4-(trifluoromethoxy) phenyl) quinolin-2-amine by selecting a patient as disclosed in the steps above by Tazi for the treatment of stomach cancer, colorectal cancer, pancreas cancer, lung cancer, and liver cancer as disclosed by Roux because the skilled artisan would have recognized Tazi’s teaching of 8-chloro-N-( 4-(trifluoromethoxy) phenyl) quinolin-2-amine and type B oncoviruses which are inducers of mammary tumors share the same compound structure disclosed by Roux who also disclosed 8-chloro-N-( 4-(trifluoromethoxy) phenyl) quinolin-2-amine and its use in treating breast cancer.
It would have then been prima facie obvious to administer 8-chloro-N-(4-(trifluoromethoxy) phenyl) quinolin-2-amine to a patient with stomach, colorectal, pancreas, or liver cancer using the criteria disclosed by Tazi to the diseases Roux disclosed were treatable with 8-chloro-N-(4-(trifluoromethoxy) phenyl) quinolin-2-amine with the reasonable expectation of success in treating those cancers. See MPEP 2144.07
Regarding the arguments of claim 34, in response to applicant's argument that claim 34 shows improved efficacy of 8-chloro-N-(4-(trifluoromethoxy)pheny1)quinolin-2-amine (obefazimod) in treating stomach cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, pancreas cancer, lung cancer, and liver cancer as compared to compound 37 of Roux (named compound 26 in the present application) and therefore constitute unexpected results, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Support for claims of unexpected results are found in the specification:
“In addition, from the results explained in the experimental part, it comes out that unexpectedly the compounds of formula (lb') or anyone of its metabolite or a pharmaceutically acceptable salt thereof are more efficient for treating and/ or preventing cancer, in particular in patients having a pre-cancerous condition, an early stage cancer or a non-metastatic cancer, than comparative compound 26 which belongs to formula (Ia) as defined in the present text and in WO2010/143168.
Indeed, in WO2010/143168, compound 26 corresponds to compound 37. And in WO2010/143168, it has been demonstrated that this compound possesses an anti-invasive effect predictive for its activity against cancer. Consequently, it was unexpected that compound 26 as defined in the present text was less efficient than compounds of formula (lb'). These results also demonstrate that a compound which has anti-invasive properties does not mandatorily have as efficient activity against a pre-cancerous condition, an early stage cancer or a non-metastatic cancer.” (pg. 44, line 28, through pg. 45 line11), and
“In addition, from these results, it comes out that unexpectedly the compounds according to the invention, more particularly compounds of formula (lb') or anyone of its metabolite or a pharmaceutically acceptable salt thereof are more efficient for treating and/or preventing cancer, in particular in patients having a pre-cancerous condition, an early stage cancer or a non-metastatic cancer, than comparative compound 26 belonging to formula (Ia) (for cell line Large intestine/Colorectum CR3085: IC50 = 0.08 versus 0.17; and for cell line stomach GA0060: IC50 = 0.6 versus higher than 10).” (Specification, pg. 105, lines 9-15).
In addition to the arguments disclosed above, the Examiner notes that the unexpected results claimed by applicant over WO2010/143168 (Tazi) are drawn to a comparison of Tazi’s compound 26 (not Tazi’s compound 90) and applicant’s compounds of formula Ib’(a Markush group of compounds). The declaration of 8-chloro-N-(4-(trifluoromethoxy) phenyl) quinolin-2-amine (obefazimod) is in regard to compound 37 (8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)guinolin-2-amine) of Roux and not compound 90 (8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine) of Roux, for which the 103 rejection is based. The examiner also note the structures of Roux’s compound 90 and applicants declaration and instant claim 1 of 8-chloro-N-(4-(trifluoromethoxy) phenyl) quinolin-2-amine (obefazimod) are structurally identical.
Conclusion
All claims are rejected, no claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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